| Nanotechnology are rapidly developing in 21st century,a variety of nanomaterials'products have been appeared in our daily life.Silver nanoparticles(AgNPs)exhibits remarkably unusual physical,chemical and biological properties,and it is widely used in medical and biological fields due to the good broad-spectrum antibacterial property.With the increasing commercialization of AgNPs,the way of exposed AgNPs for people to become diversified.At present,lots of in vitro studies on biological effects and toxicity evaluation of AgNPs.In vivo studies of AgNPs are not abundant enough.Biological effects and kinetics reaserch of AgNPs in vivo are necessary for the toxicity.It is necessary to research a tool or method to integrate various experimental data and information which can be more scientific and rational application of AgNPs research in vivo and in vitro data.Physiologically based toxicokinetic(PBTK)model is based on physiology and anatomy.Bloodstream was used to contact each organ and tissue.The model reflected the process of poison distribution,conversion,metabolism and excretion.Constructed the equations to describe changing process according to the mass conservation rule.The relation between concentration and time in the organization or organ could be described after solving system of equations.It could effectively describe the change of toxic in vivo,and predict the target dose.Three kinds of different silver nanoparticles,AgNPs-20 and AgNPs-50(20nm,50nm,99.99%silver content),AgNPs-PVP(20nm,PVP coated,25%silver content),were used to research the biokinetics of silver nanoparticles in vitro.AgNPs-20 and AgNPs-PVP were used to expose mice by short term duplicate twenty-eight days oral to study the subacute toxicity of silver nanoparticles.Based on the above research,collecting the physiological and biochemical parameters in mice by literature search.Then using Matrix laboratory(MATLAB)software to solve the differential equations of each organ.At last,the distribution data in vivo was used to validate and optimize the model.1?Characterization of silver nanomaterials and biokinetics of silver nanoparticles in vitro.The morphology results of three kinds AgNPs were in spherical shape.AgNPs-PVP showed better dispersibility.The average particle size and hydrated particle size were respectively 22.08±4.74nm and 64.27±21.42nm.Silver content of the material was 25.48%.AgNPs-20 and AgNPs-50 showed ellipsoid.The average particle size and hydrated particle size were respectively 20.14±3.67nm and 49.84±8.02nm,542.73±64.83nm and 912.34±76.25nm.Silver content of AgNPs-20 and AgNPs-50were respectively98.97%and 99.53%.The results of biokinetics in vitro showed that silver ions could released from three kinds AgNPs in different pH(3.6,6.0 and 7.0)solutions and showed positively correlated with the dose and time.The content of silver ions only showed positively correlated with the dose in the cell culture medium.The content of silver ions released from AgNPs-PVP was significantly higher than that the non-coated silver nanoparticles at the same dose(P<0.05).At the same time,the ratio of silver ions in pure water was higher than that of the other three solutions.Indicating that the content of silver ions released from AgNPs was affected by coating,dose,pH and time.2?Subacute toxicity of silver nanoparticles in mice.Mice were exposed AgNPs-PVP and AgNPs-20 by oral for twenty-eight days.The dose were respectively 10mg/kg,50mg/kg and 250 mg/kg.Control group was exposed HPMC(hydroxyl propyl methyl cellulose)and AgNO3 by the dose of 1%and 5mg/kg.The influence of the ordinary index showed that compared with HPMC group,the mice of the groups with 250mg/kg became bradypsychia and retrain the increasing weights.The influence of the relative organ weight showed that compared with HPMC group,the mice of all groups with AgNO3 and silver nanoparticles increased in viscera coefficient of lung,liver,kidney,spleen and brain significantly(P<0.05).Serum biochemical index:Compared with HPMC group,the TP,ALT and AST of AgNO3 and 250mg/ml groups increased(P<0.05).There was no significant difference compared to other indicators with HPMC group.The serum biochemical changes indicate the subacute toxicity after exposed two kinds AgNPs with 250mg/kg by oral.Histopathology watch:Compared with HPMC group the mices' of AgNO3 and two kinds of AgNPs had different degree of pathological changes with lung,liver,spleen and kidney.There are obvious pathological changes which with slight inflammatory reaction in liver and lung.The reducing of pathological changes as the extension of observation time,pertaining that there is a certain self-healing in mice.3?Mices biodistribution and excretion research:Mice were exposed by oral for twenty-eight days after exposed for several time(ld,7d,14d,21d and 28d).Blood,organ,feces and urine samples were taken.The content of silver showed positively correlated with the dose and negatively correlated with the time in all samples.Silver concentration in the blood of AgNPs groups were in rapid decline in 7d and became stable in 7d to 28d after exposure.AgNPs-PVP and AgNPs-20 mainly distributed in the liver and spleen.There is a certain amount of silver was detected in the brain.Indicating that the AgNPs can be absorbed into the blood through the gastrointestinal tract,then could widely distribute in various organs.And AgNPs can through the blood-brain barrier into the brain tissue.The content of silver in feces is about 500 times than in urine,indicating that feces is the main pathway for the excretion of AgNPs in mice.4?Construction and validation of PBTK model.Making a reasonable model hypothesis based on the physiological process of in mice.Physiological parameters of mice and biochemical parameters of AgNPs were collected by reviewing literature to establishing the structure of model and building differential equations.Biochemical parameters are optimized by ACSLX,and then the differential equations solved by MATLAB.The existing.data of AgNPs in mice was applied to validate the model.The AgNPs-PVP 1Omg/kg group fitting data of heart and other organs Pearson correlation coefficient were respectively about 0.8 and 0.9.The model of actual data fitting is good.In conclusion,the content of silver ions released from AgNPs was affected by coating,dose,pH and time.Weight,viscera coefficient,serum biochemical and histopathological changes indicate the subacute toxicity after exposed AgNPs-PVP and AgNPs-20 with 250mg/kg by oral.The main target organ was liver,and there is a self-healing capability for mice to the toxicity of AgNPs.The main accumulate organs of the AgNPs are liver and spleen in mice,and the AgNPs can through the blood-brain barrier into the brain tissue.Excretion shows that AgNPs mainly excrete through feces.The results of Pearson correlation coefficient showed that the PBTK model can preliminary simulate the metabolism of AgNPs in mice with better fitting.This model can preliminary extrapolation after optimized several parameters,and then provides the data support for biosafety assessment of AgNPs. |
PDF Full Text Request